Autoimmune-Induced Glutamatergic Receptor Dysfunction Methods and Treatments

ABSTRACT

This invention provides a method of enhancing NMDAR-mediated neurotransmission in a disease associated with NMDAR antibody production, said method comprising administering an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor or a combination thereof to said subject. This invention also provides a method of mitigating the severity of, mitigating the pathogenesis of, lowering the incidence of or treating a disease associated with NMDAR antibody production, said method comprising administering an agent, which is an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor or a combination thereof to said subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/893,992, filed Nov. 25, 2015, which is a US national stage entry ofPCT/IL2014/050474, filed May 26, 2014, which claims the benefit of U.S.Provisional Application No. 61/827,764, filed May 28, 2013; and theseforegoing applications are all incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical compositions for thetreatment of autoimmune-induced glutamatergic receptor dysfunction anddisorders related to same. More particularly, the present inventionrelates to the use of N-methyl-D-aspartate type glutamate receptor(NMDAR) agonists (NMDAR agonists, also known as NMDA agonists) andpartial agonists for the treatment of autoimmune-induced glutamatergicreceptor encephalitis.

NMDAR are a type of receptor for the excitatory neurotransmitterglutamate. NMDAR contain additional modulatory sites, including thefollowing: glycine binding site, polyamine binding site, redox site,Zinc (Zn) site, phosphorylation sites, post-synaptic membrane dockingsites and protein-protein interaction sites. The glycine binding site issensitive to monocarboxyllic amino acids including the endogenous aminoacids glycineD-serine and D-alanine. Glycine is synthesized via serineor threonine by serine hydroxymethyltransferase. Synaptic glycineconcentrations are regulated by type 1 (GLYT1) and type 2 (GLYT2)glycine transporters, as well as by other amino acid transportersbelonging to Systems A, L, ASC, and N.

GLYT1 transport inhibitors, such asN[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy) propyl]sarcosine (NFPS),potentiate NMDAR activity in vivo, suggesting a critical role forglycine transporters in NMDAR regulation. Methylated glycine derivates(e.g., methylglycine, sarcosine) may serve as non-specific glycinetransport inhibitors D-serine and D-alanine are metabolized by D-aminoacid oxidase (DAAO), which is localized particularly in hindbrain.Further, DAAO is regulated by a novel protein termed G72, which mayaffect metabolic activity of the DAAO enzyme.

Glycine, D-serine and D-alanine levels in brain may be modulated byadministering exogenous compound (i.e., glycine, D-serine or D-alanine),or naturally occurring precursors to these compounds including but notlimited to L-serine, L-phosphoserine, D-phosphoserine and threonine, orby modulation of the synthetic enzymes serine hydroxymethyltransferaseor serine racemase. D-Serine or D-alanine levels may also be increasedby modulation inhibiting D-serine or D-alanine breakdown, for example,by antagonizing DAAO activity either directly or indirectly (e.g., viamodulatory proteins).

Limbic encephalitis (LE) refers to an inflammatory process thatpredominantly affects the grey matter of the medial temporal lobes,amygdala and orbito-frontal cortex and produces cognitive impairmentalong with emotional and behavioral disturbances, sleep disruption,seizures and sometimes dementia. Until recently, autoimmune LE wasmostly viewed as a paraneoplastic disorder associated with onconeuralantibodies to intracellular antigens, cytotoxic T-cell mediatedpathogenesis and limited response to treatment. However, accumulatingdata suggest that the clinical and immunological spectra of LE are farmore extensive than initially considered. During the last decade a novelcategory of autoimmune encephalitides has emerged, that is characterizedby antibodies against neuronal cell surface antigens, less frequentassociation with cancer, an antibody-mediated pathogenesis and improvedtreatment response following immunotherapy. Receptors and proteins thatare critically involved in glutamatergic neurotransmission and synapticplasticity, including N-methyl-D-aspartate andalpha-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptors(NMDAR, AMPAR) are cardinal target antigens in many of these disorders.Characteristic of these syndromes, the antibodies alter the structureand/or function of the corresponding neuronal antigen resulting inclinical pictures that resemble the pharmacological or genetic models inwhich the antigen is disrupted. Given the involvement of glutamatergicneurotransmission in a variety of psychiatric disorders, includingschizophrenia and affective disorders, the identification of specificautoimmune-induced glutamatergic receptor dysfunctions (AGRD) is likelyto have a substantial conceptual impact upon our understanding ofneuropsychiatric disorders and to provide additional guidance forpsychiatric diagnostics and treatments development.

NMDAR play a key role in the regulation of movement and striatalfunction and in the modulation of executive functions and effect. NMDARsare found on multiple classes of neuron within striatum includingprojection neurons and internuerons. NMDARs are composed of multiplesubunits including an NR1 subunit which is present in virtually allfunctional NMDARs, and NR2 subunits that are present in variableproportions. Four NR2 subunits (NR2A-D) have been described. NR2Aexpression is high in GABAergic neurons that express the marker GAD67,intermediate over SP neurons, low in ENK neurons, not found incholinergic and SOM neurons. In contrast, NR2B expression is intense inall populations of neurons, while expression of NR2C,D is weak

The existence of multiple subforms of NMDAR in striatum is supported bythe observation that NMDARs controlling GABA and DA release are lesssensitive to NMDA than receptors controlling spermidine or ACh release.

Anti-NMDAR encephalitis is an autoimmune encephalitis characterized bythe presence of antibodies against synaptic NMDAR. Anti-NMDARencephalitis has become the most common and best characterizedantibody-defined autoimmune neuronal disorder. Nevertheless, additionalAGRD syndromes, associated with the presence of antibodies againstdiverse GLU neurotransmission—related antigens, including differentNMDAR subunits, AMPAR and metabotropic receptor proteins are beingincreasingly characterized. Furthermore, the presence of NMDAR and AMPARdirected antibodies in conjunction with antibodies to different othertypes of receptors and neurotransmission systems has been reported.Overall, in view of the impact and interest generated by these findings,it is likely that during the next decade we will witness a significantexpansion in the identification, characterization and understanding ofAGRD.

The encephalitis associated with antibodies against NMDAR predominantlyaffects children and young adults, occurs with or without tumorassociation, responds to treatment but can relapse. The presence of atumor (usually an ovarian teratoma) is dependent on age, sex andethnicity, being more frequent in women older than 18 years and blackwomen.

The exact incidence of anti-NMDAR encephalitis is unknown but it seemsto be more frequent than any other known paraneoplastic encephalitis.Furthermore, due to the rareness of the syndrome and the varied clinicalpresentations ranging from psychiatric and neurological manifestationsto autonomic dysregulation, the anti-NMDAR syndrome is stillmisdiagnosed and under-recognized.

Few laboratory diagnostic tests are available for anti-NMDARencephalitis and related syndromes. The most accurate diagnostic findingis the presence of antibodies against NMDAR in the serum or CSF. Serumand CSF of patients suspected with the syndrome should be checked forreactivity with the hippocampal tissue on rat brain sections,cell-surface labeling of cultured hippocampal neurons, or reactivitywith NR1/NR2 transfected human embryonic kidney (HEK) cells. The CSF mayalso present pleocytosis, increased protein concentration, oligoclonalbands and high IgG index. In vitro and in vivo studies demonstrate thatpatients antibodies decrease the surface density and synapticlocalization of NMDAR clusters via antibody mediated capping andinternalization, independent of the presence of complement, and withoutaffecting other synaptic proteins, AMPARs or synapse density. Themagnitude of these changes depends on antibody titer, and the effectsare reversible when the antibody titer is reduced. Moreover, patientsNR1 antibodies decrease NMDAR-, but not AMPAR-mediated synapticcurrents.

This reversible NMDARs loss, and the resulting synaptic dysfunction, mayunderlie the deficits in memory, behavior and cognition that arehallmarks of anti-NMDAR encephalitis. Indeed, a remarkable feature ofthis disorder is the frequent reversibility of symptoms, even when theseare severe and protracted. A decrease in serum antibody titers wasdemonstrated in parallel to immuno-modulatory treatment and clinicalremission. Consequently, the effectiveness of therapeutic strategies maybe assessed individually by quantitative determination of anti-NMDARantibodies.

Other tests that can be done to support the diagnosis areelectroencephalogram and MRI. Electroencephalogram can frequentlydemonstrate focal or diffuse slow activity during episodes ofdyskinesias or abnormal movements and less commonly it may showepileptic activity. In many patients, MRI shows small areas of FluidAttenuated Inversion Recovery (FLAIR) abnormalities in cerebral cortexoutside the medial temporal lobes, sometimes involving the cerebellumand brainstem or transient enhancement of overlying meninges.

Immunotherapy and the detection and removal of a tumor (mostly teratoma)are the most important components in the treatment of anti-NMDARencephalitis. Rosenfeld and Dalmau have proposed a structured treatmentapproach to patients with synaptic autoimmunities such as anti-NMDARencephalitis. First, search for and remove a tumor. After tumor removalor if no tumor is found, 5-days course of concurrent IV Ig and methylprednisolone should be given. If clear improvement is seen within 10days, supportive care should be continued. If there is no response orlimited response after one cycle of immunosuppression, cyclophosphamide(monthly) and rituximab (weekly for 4 weeks starting with the first doseof cyclophosphamide) should be initiated. For patients with limited orno response to these approaches, other forms of immunosuppression shouldbe considered. For patients without tumors, immunosuppression withmycophenolate mofetil or azathioprine for at least one year afterinitial treatments should be considered, to reduce the high rate ofrelapses after recovery.

In patients without a tumor or with delayed diagnosis, additionaltreatment with second-line immunotherapy (rituximab or cyclophosphamide,or both) is usually needed with equivocal results. Relapses ofanti-NMDAR encephalitis occur in 20% to 25% of treated patients, aswell.

An accepted treatment of the syndrome is immunomodulation, whichinadequately addresses the alleviation of psychiatric manifestations.There are several documented cases of neuroleptic administrationactually exacerbating neuropsychiatric symptoms and movementabnormalities. ECT has been used for targeting catatonic presentationsin patients with autoimmune encephalitis, including anti-NMDARencephalitis. Agitated aggression has been treated with variousconventional and atypical antipsychotics with limited treatmentresponse. Atypical antipsychotics have also been used to targetpsychotic symptoms without significant success and have the potential toworsen dyskinesia and other movement abnormalities.

Thus there remains a need for the development of an appropriatetherapeutic for encephalitis associated with antibodies against NMDAR,which is as yet lacking.

SUMMARY OF THE INVENTION

NMDAR agonist treatment significantly improves quality of life insubjects suffering from encephalitis associated with antibodies againstNMDAR or other diseases whose pathogenesis is associated with thepresence of antibodies against NMDAR, including reducing psychopathologysymptoms, improving motor symptomatology and improving cognitiveperformance, including improving working memory, abstraction and mentalflexibility.

This invention provides a method for enhancing NMDAR-mediatedneurotransmission for encephalitis associated with antibodies againstNMDAR or other diseases whose pathogenesis is associated with thepresence of antibodies against NMDAR. In some embodiments, the inventioncontemplates use of glycine (GLY), D-Serine (DSR) or D-cycloserine(DCS), or combinations thereof, for their agonist activity for theNMDAR-associated GLY site in connection therewith. In some embodiments,the invention contemplates use of GLY transport inhibitors and D-aminoacid oxidase inhibitors in connection therewith. In some embodiments theinvention contemplates use of alanine-serine-cysteine transporter (ASCT)inhibitors and in some embodiments, the invention contemplates use ofD-serine transporter inhibitors in connection therewith.

The present invention also provides for the use of an NMDAR agonist orpartial agonist in the manufacture of a pharmaceutical composition,medical food, or dietary supplement for the treatment of encephalitisassociated with antibodies against NMDAR or other diseases whosepathogenesis is associated with the presence of antibodies againstNMDAR.

All publications, patents, and patent applications mentioned herein arehereby incorporated by reference in their entirety as if each individualpublication or patent was specifically and individually indicated to beincorporated by reference. In case of a conflict between thespecification and an incorporated reference, the specification shallcontrol. Where number ranges are given in this document, endpoints areincluded within the range. Furthermore, it is to be understood thatunless otherwise indicated or otherwise evident from the context andunderstanding of one of ordinary skill in the art, values that areexpressed as ranges can assume any specific value or sub-range withinthe stated ranges, optionally including or excluding either or bothendpoints, in different embodiments of the invention, to the tenth ofthe unit of the lower limit of the range, unless the context clearlydictates otherwise. Where a percentage is recited in reference to avalue that intrinsically has units that are whole numbers, any resultingfraction may be rounded to the nearest whole number.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 demonstrates the reduction of an extreme delta brush (EDB)pattern after six weeks of D-Serine (DSR) therapy in a patient positivefor the presence of anti-NR1 NMDAR antibodies. Pre- and Post-treatmenteffects are shown, as designated. Electroencephalogram (EEG) resultswith eyes opened are shown in FIG. 1. Normal EEG background activitywith superimposed semi-rhythmic diffuse delta frequency bursts morepredominantly over the right frontal-temporal areas, characteristic ofEDB is seen prior to treatment, that is significantly reduced posttreatment.

FIG. 2 demonstrates the reduction of an extreme delta brush (EDB)pattern after six weeks of D-Serine (DSR) therapy in a patient positivefor the presence of anti-NR1 NMDAR antibodies. Pre- and Post-treatmenteffects are shown, as designated. Electroencephalogram (EEG) resultswith eyes opened are shown in FIG. 2. Normal EEG background activitywith superimposed semi-rhythmic diffuse delta frequency bursts morepredominantly over the right frontal-temporal areas, characteristic ofEDB is seen prior to treatment, that is significantly reduced posttreatment.

FIG. 3 shows the average spectra of EDB in the frontal region (F8channel; thick line—average, thin line—SD) showing reduction in currentlatency post-treatment as compared to pre-treatment values (uV at 500msec, lighter line), P=0.0083 t-test, two-tailed.

FIG. 4A shows electroencephalogram (EEG) coherence values pre- andpost-six weeks of D-serine administration in the same patient,respectively. Light gray lines indicate the amount of coherence betweenelectrodes. Distinct new patterns of EEG coherence are present followingDSR treatment, across all frequency bands. Channel abbreviations:frontal (Fz,F3,F4), central (Cz,C3,C4), temporal (T7), parietal(Pz,P7,P3,P4), occipital (O1,O2) brain regions.

FIG. 4B shows electroencephalogram (EEG) coherence values pre- andpost-six weeks of D-serine administration in the same patient,respectively. Light gray lines indicate the amount of coherence betweenelectrodes. Distinct new patterns of EEG coherence are present followingDSR treatment, across all frequency bands. Channel abbreviations:frontal (Fz,F3,F4), central (Cz,C3,C4), temporal (T7), parietal(Pz,P7,P3,P4), occipital (O1,O2) brain regions.

FIG. 4C shows electroencephalogram (EEG) coherence values pre- andpost-six weeks of D-serine administration in the same patient,respectively. Light gray lines indicate the amount of coherence betweenelectrodes. Distinct new patterns of EEG coherence are present followingDSR treatment, across all frequency bands. Channel abbreviations:frontal (Fz,F3,F4), central (Cz,C3,C4), temporal (T7), parietal(Pz,P7,P3,P4), occipital (O1,O2) brain regions.

FIG. 4D shows electroencephalogram (EEG) coherence values pre- andpost-six weeks of D-serine administration in the same patient,respectively. Light gray lines indicate the amount of coherence betweenelectrodes. Distinct new patterns of EEG coherence are present followingDSR treatment, across all frequency bands. Channel abbreviations:frontal (Fz,F3,F4), central (Cz,C3,C4), temporal (T7), parietal(Pz,P7,P3,P4), occipital (O1,O2) brain regions.

FIG. 5A shows electroencephalogram (EEG) coherence values pre- andpost-six weeks of D-serine administration in the same patient,respectively. Light gray lines indicate the amount of coherence betweenelectrodes. Distinct new patterns of EEG coherence are present followingDSR treatment, across all frequency bands. Channel abbreviations:frontal (Fz,F3,F4), central (Cz,C3,C4), temporal (T7), parietal(Pz,P7,P3,P4), occipital (O1,O2) brain regions.

FIG. 5B shows electroencephalogram (EEG) coherence values pre- andpost-six weeks of D-serine administration in the same patient,respectively. Light gray lines indicate the amount of coherence betweenelectrodes. Distinct new patterns of EEG coherence are present followingDSR treatment, across all frequency bands. Channel abbreviations:frontal (Fz,F3,F4), central (Cz,C3,C4), temporal (T7), parietal(Pz,P7,P3,P4), occipital (O1,O2) brain regions.

FIG. 5C shows electroencephalogram (EEG) coherence values pre- andpost-six weeks of D-serine administration in the same patient,respectively. Light gray lines indicate the amount of coherence betweenelectrodes. Distinct new patterns of EEG coherence are present followingDSR treatment, across all frequency bands. Channel abbreviations:frontal (Fz,F3,F4), central (Cz,C3,C4), temporal (T7), parietal(Pz,P7,P3,P4), occipital (O1,O2) brain regions.

FIG. 5D shows electroencephalogram (EEG) coherence values pre- andpost-six weeks of D-serine administration in the same patient,respectively. Light gray lines indicate the amount of coherence betweenelectrodes. Distinct new patterns of EEG coherence are present followingDSR treatment, across all frequency bands. Channel abbreviations:frontal (Fz,F3,F4), central (Cz,C3,C4), temporal (T7), parietal(Pz,P7,P3,P4), occipital (O1,O2) brain regions.

DETAILED DESCRIPTION OF THE INVENTION

While the invention will now be described in connection with certainpreferred embodiments in the following examples so that aspects thereofmay be more fully understood and appreciated, it is not intended tolimit the invention to these particular embodiments. On the contrary, itis intended to cover all alternatives, modifications and equivalents asmay be included within the scope of the invention as defined by theappended claims.

This invention provides a method of enhancing NMDAR-mediatedneurotransmission in a disease associated with NMDAR antibodyproduction, said method comprising administering an NMDAR agonist, analanine-serine-cysteine transporter inhibitor, a D-amino acid oxidaseinhibitor, a glycine transport inhibitor, a partial agonist such asD-cycloserine or a combination thereof to said subject.

This invention also provides a method of mitigating the severity of,mitigating the pathogenesis of, lowering the incidence of and/ortreating a disease associated with NMDAR antibody production, saidmethod comprising administering an agent, which is an NMDAR agonist, analanine-serine-cysteine transporter inhibitor, a D-amino acid oxidaseinhibitor, a glycine transport inhibitor, D-cycloserine or a combinationthereof to said subject.

In some embodiments, the disease associated with NMDAR antibodyproduction is paraneoplastic autoimmune encephalitis. In someembodiments, the disease associated with NMDAR antibody production isnon-paraneoplastic autoimmune encephalitis. In some embodiments, thedisease associated with NMDAR antibody production is anti-NMDARencephalitis.

In some embodiments, the methods include identification of a subjectwith a disease associated with NMDAR antibody production. In someembodiments, according to this aspect, such methods include assessingqualitative or quantitative levels of NMDAR antibodies in a biologicalsample from a suspected subject. In some embodiments, the biologicalsample used in the methods described herein is a body fluid that is, inanother embodiment, a cerebro-spinal fluid (CSF). In another embodiment,the body fluid is plasma. In another embodiment, the body fluid is anyother type of fluid known in the art. Each possibility represents aseparate embodiment of the present invention. In another embodiment, thebiological sample is amniotic fluids, blood, sera, saliva, or theircombination in another embodiment.

In some embodiments, the methods include identification of a subjectwith a disease associated with NMDAR antibody production by assessingother neurologic or psychiatric symptomatology. In one embodiment,encephalitis causes deficits that are characteristically dominated byrapid and severe loss of short-term memory. In another embodiment,patients show encephalitis with evidence of cancer.

In another embodiment, the encephalitis is associated with seizures. Inanother embodiment, the encephalitis is associated with a diencephalicsyndrome. In another embodiment, the encephalitis is associated with apsychiatric symptom. In another embodiment, the encephalitis isassociated with an abnormality in cognition. In another embodiment thethe encephalitis is associated with an abnormality in cognition. Inanother embodiment, the encephalitis is associated with an abnormalityin behavior. In another embodiment, the encephalitis is associated withamnesia. In another embodiment, the encephalitis is associated with amemory deficit. In another embodiment, the encephalitis is associatedwith memory problems. In another embodiment, the encephalitis isassociated with a hypokinetic syndrome.

In another embodiment, the encephalitis is associated with a movementdisorder. In another embodiment, the encephalitis is associated withabnormal movements. In another embodiment, the movement disorder isStiff Man/Person Syndrome. In another embodiment, the movement disorderis any other movement disorder known in the art. Each possibilityrepresents a separate embodiment of the present invention.

In another embodiment, the encephalitis is associated with a decreasedlevel of consciousness. In another embodiment, the encephalitis isassociated with hypoventilation.

In another embodiment, the encephalitis is associated with, dysfunctionof any part of the brain or spinal cord. In another embodiment, theencephalitis is associated with a combination of any of the abovesymptoms or disorders.

In another embodiment, the encephalitis is associated with a tumor. Inanother embodiment, the tumor is an ovarian teratoma. In anotherembodiment, the tumor is a thymic tumor. In another embodiment, thetumor is a testicular tumor. In another embodiment, the cancerassociated with the encephalitis is a cervical cancer tumor. In anotherembodiment, the cancer is a head and neck cancer tumor. In anotherembodiment, the cancer is a breast cancer tumor. In another embodiment,the cancer is an ano-genital cancer tumor. In another embodiment, thecancer is a melanoma. In another embodiment, the cancer is a sarcoma. Inanother embodiment, the cancer is a carcinoma. In another embodiment,the cancer is a lymphoma. In another embodiment, the cancer is aleukemia. In another embodiment, the cancer is mesothelioma. In anotherembodiment, the cancer is a glioma. In another embodiment, the cancer isa germ cell tumor. In another embodiment, the cancer is achoriocarcinoma.

In another embodiment, the cancer is pancreatic cancer. In anotherembodiment, the cancer is ovarian cancer. In another embodiment, thecancer is gastric cancer. In another embodiment, the cancer is acarcinomatous lesion of the pancreas. In another embodiment, the canceris pulmonary adenocarcinoma. In another embodiment, the cancer iscolorectal adenocarcinoma. In another embodiment, the cancer ispulmonary squamous adenocarcinoma. In another embodiment, the cancer isgastric adenocarcinoma. In another embodiment, the cancer is an ovariansurface epithelial neoplasm (e.g. a benign, proliferative or malignantvariety thereof). In another embodiment, the cancer is an oral squamouscell carcinoma. In another embodiment, the cancer is nonsmall-cell lungcarcinoma. In another embodiment, the cancer is an endometrialcarcinoma. In another embodiment, the cancer is a bladder cancer. Inanother embodiment, the cancer is a head and neck cancer. In anotherembodiment, the cancer is a prostate carcinoma.

In another embodiment, the cancer is an acute myelogenous leukemia(AML). In another embodiment, the cancer is a myelodysplastic syndrome(MDS). In another embodiment, the cancer is a non-small cell lung cancer(NSCLC). In another embodiment, the cancer is a Wilms' tumor. In anotherembodiment, the cancer is a leukemia. In another embodiment, the canceris a lymphoma. In another embodiment, the cancer is a desmoplastic smallround cell tumor. In another embodiment, the cancer is a mesothelioma(e.g. malignant mesothelioma). In another embodiment, the cancer is agastric cancer. In another embodiment, the cancer is a colon cancer. Inanother embodiment, the cancer is a lung cancer. In another embodiment,the cancer is a breast cancer. In another embodiment, the cancer is agerm cell tumor. In another embodiment, the cancer is an ovarian cancer.In another embodiment, the cancer is a uterine cancer. In anotherembodiment, the cancer is a thyroid cancer. In another embodiment, thecancer is a hepatocellular carcinoma. In another embodiment, the canceris a thyroid cancer. In another embodiment, the cancer is a livercancer. In another embodiment, the cancer is a renal cancer. In anotherembodiment, the cancer is a kaposis. In another embodiment, the canceris a sarcoma. In another embodiment, the cancer is another carcinoma orsarcoma.

In another embodiment, the tumor is any other type of tumor known in theart.

Methods for diagnosing encephalitis are well known in the art. Inanother embodiment, patients with encephalitis develop subacuteconfusion, irritability, depression, sleep disturbances, seizures,short-term memory loss, and/or dementia. In another embodiment, thepathological substrate of encephalitis is an inflammatory disorder thatinvolves the limbic system (hippocampi, amygdala, and cingulate gyrus).In another embodiment, biopsy and autopsy studies demonstrateinterstitial and perivascular infiltrates of T cells, and lessfrequently B cells, along with microglial activation, neuronaldegeneration, and/or gliosis. In another embodiment, inflammatoryinfiltrates are found in areas distant from the limbic system. Inanother embodiment, the infiltrates remain mild and clinically silent.In another embodiment, the infiltrates become prominent and develop intoa disorder called encephalomyelitis. Additional methods of diagnosingencephalitis are described, for example, in Gultekin S H et al (Brain2000; 123:1481-1494). Each possibility represents a separate embodimentof the present invention.

In some embodiments the method further comprises the step of removingthe tumor, providing immunotherapy or a combination thereof.

Agents may be screened for effectiveness in stimulating NMDAtransmission in vitro using assays, for example, measuring modulation ofNMDAR-mediated activity in hippocampal slices or of NMDAR-stimulateddopamine release in isolated mouse striatum. Agents may be screened invivo using assays, for example, measuring amphetamine induced dopaminerelease or NMDAR-mediated electrophysiological activity. Agents will beeffective in ameliorating movement disorders at doses sufficient topotentiate NMDAR-mediated neurotransmission in vivo.

In addition to the embodiments listed above, prodrugs may also beadministered. Prodrugs are defined as agents that are not themselvesagonists of the NMDAR, but which enter the brain and are converted ormetabolized there into effective agonists. An example of a glycineprodrug is milacemide. Simple precursors can be made by esterification,alkylation or other linkage, most effectively to hydrophobic groups thatincrease lipophilicity and diffusion into CNS.

In a preferred embodiment of the invention, NMDAR agonists, includingbut not limited to glycine, D-serine, or D-alanine, are conjugated tomolecules that are actively transported into the CNS, leading toincreased central penetration. Precursors to glycine, D-serine orD-alanine, including threonine, L-phosphoserine and D-phosphoserine, mayalso be incorporated into prodrugs.

In another aspect, the methods of the invention are useful in confirmingsuspected encephalitis associated with antibodies against NMDAR or otherdiseases whose pathogenesis is associated with the presence ofantibodies against NMDAR, which method comprises confirming saidencephalitis associated with antibodies against NMDAR or other diseaseswhose pathogenesis is associated with the presence of antibodies againstNMDAR, as a result of a positive response by any of the indicia hereindescribed, to treatment with an NMDAR agonist, analanine-serine-cysteine transporter inhibitor, a D-amino acid oxidaseinhibitor, a glycine transport inhibitor, a partial agonist such asD-cycloserine or a combination thereof.

The pharmaceutical compositions can be administered to the patient byany, or a combination, of several routes, such as oral, intravenous,trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary, transdermal,ocular, buccal, sublingual, intraperitoneal, intrathecal, intramuscular,or long term depot preparation. Solid compositions for oraladministration can contain suitable carriers or excipients, such as cornstarch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose,kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodiumchloride, lipids, alginic acid, or ingredients for controlled slowrelease. Disintegrators that can be used include, without limitation,micro-crystalline cellulose, corn starch, sodium starch glycolate andalginic acid.

Tablet binders that may be used include, without limitation, acacia,methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone(Povidone), hydroxypropyl methylcellulose, sucrose, starch, andethylcellulose.

Liquid compositions for oral administration prepared in water or otheraqueous vehicles can include solutions, emulsions, syrups, and elixirscontaining, together with the active compound(s), wetting agents,sweeteners, coloring agents, and flavoring agents. Various liquid andpowder compositions can be prepared by conventional methods forinhalation into the lungs of the patient to be treated.

Injectable compositions may contain various carriers such as vegetableoils, dimethylacetamide, dimethylformamide, ethyl lactate, ethylcarbonate, isopropyl myristate, ethanol, polyols (glycerol, propyleneglycol, liquid polyethylene glycol, and the like). For intravenousinjections, the compounds may be administered by the drip method,whereby a pharmaceutical composition containing the active compound(s)and a physiologically acceptable excipient is infused. Physiologicallyacceptable excipients may include, for example, 5% dextrose, 0.9%saline, Ringer's solution or other suitable excipients.

For intramuscular preparations, a sterile composition of a suitablesoluble salt form of the compound can be dissolved and administered in apharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5%glucose solution, or depot forms of the compounds (e.g., decanoate,palmitate, undecylenic, enanthate) can be dissolved in sesame oil.Alternatively, the pharmaceutical composition can be formulated as achewing gum, lollipop, or the like.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the solid substrates, kits,process and methods of the present invention without departing from thespirit or scope of the invention.

In some embodiments, the term “comprise” or grammatical forms thereof,refers to the inclusion of the indicated components of this invention,as well as inclusion of other active agents, and pharmaceuticallyacceptable carriers, excipients, emollients, stabilizers, etc., as areknown in the pharmaceutical industry.

In one embodiment, the term “about” refers to a variance of from 1-10%,or in another embodiment, 5-15%, or in another embodiment, up to 10%, orin another embodiment, up to 25% variance from the indicated values,except where context indicates that the variance should not result in avalue exceeding 100%.

In one embodiment, the present invention provides combined preparations.In one embodiment, the term “a combined preparation” defines especiallya “kit of parts” in the sense that the combination partners as definedabove can be used independently or in different combinations i.e.,simultaneously, concurrently, separately or sequentially.

Thus, the following examples which include preferred embodiments willserve to illustrate the practice of this invention, it being understoodthat the particulars shown are by way of example and for purposes ofillustrative discussion of preferred embodiments of the presentinvention only and are presented in the cause of providing what isbelieved to be the most useful and readily understood description offormulation procedures as well as of the principles and conceptualaspects of the invention.

EXAMPLES Example 1 In Vivo Efficacy of NMDAR Agonists in Anti-NMDAREncephalitis

Anti-NMDAR encephalitis is diagnosed in a study subjects. Diagnosis isbased on a determination of the presence of NR1 IgG antibodies in theserum/CSF of the subjects.

Patients of age 18-65, diagnosed with anti-NMDAR encephalitis on thebasis of a) serum or cerebrospinal fluid (CSF) NMDAR antibody detection;and b) presentation of psychiatric and/or motor dysfunction symptomswill be assessed.

The patients will receive D-serine for 6 wks in addition to theclinically determined treatment.

Dosages of D-serine assessed will include staggered treatment regimens,including administration the first week of 1500 mg/d; and subsequentweeks, the subject will be administered a dosage of 4000 mg/d.

Changes in the assessed parameters over baseline will be recorded,including total scores of Positive and Negative Syndrome Scale andAbnormal Involuntary Movement Scale assessment, Continuous PerformanceTest, Verbal Memory Test, and Quality of Life Scale and others, as willbe known to the skilled artisan.

Following the six week assessment period, subjects treated with D-serinewill exhibit signs of improvement, as measured by significant scorereduction in Positive and Negative Syndrome Scale and AbnormalInvoluntary Movement Scale assessment, Continuous Performance Test,Verbal Memory Test, and Quality of Life Scale.

Example 2 Demonstration of Beneficial Effects of D-Serine in a PatientPositive for Anti-NR1 NMDAR Antibodies Materials and Methods PatientInclusion and Exclusion Criteria

The study was approved by the appropriate institutional review boards.Seventeen schizophrenia/schizoaffective patients fulfilled the inclusioncriteria and were enrolled in the study. After complete description ofthe study, orally and in writing, informed consent was obtained from allparticipants. In order to be included in the study patients had tofulfill the following criteria:

-   -   1—Treatment-resistance to pharmacotherapy with presently        available antipsychotic drugs and at least one of the following:    -   2—Abrupt start of disease, lack of patient/family history of        psychiatric disorders and atypical disease course.    -   3—Presence or history of hebephrenic features    -   4—Presence or history of catatonic features    -   5—Presence or history of dyskinetic features and/or fulfillment        of Schooler-Kane (1982) diagnostic criteria for tardive        dyskinesia    -   6—Presence or history of seizure unaccounted by a neurological        or other disorder.

Participants were excluded from participation in the study for any ofthe following reasons:

1) meeting criteria for DSM-IV Axis I diagnoses other thanschizophrenia/schizoaffective disorder;2) presence of a neurological disorder or history of significant headinjury;3) substance abuse or alcoholism during entire lifetime;4) were judged clinically to be at suicidal or homicidal risk;5) presence of an unstable and/or untreated medical disorder;6) presence or history of renal dysfunction; and7) female patients who were pregnant or lactating; female patients, ifsexually active, had to be using medically accepted means ofcontraception.

Antibodies Assessment

A 5cc. blood sample was obtained from each participating patient for theassessment of the presence of anti-NMDAR antibodies. Blood samples wereprior to eating and prior to the administration of any type ofmedication.

Detection of autoantibodies against extracellular epitopes of NMDAR wasperformed in each of the serum samples obtained using a previouslydescribed cell-based assay (Takano et al., 2011 Neurosci Res71:294-302). Patient serum samples were analyzed using cells expressingmutant NMDAR subunits by immunocytochemistry and on-cell Westernanalysis using live cells stably expressing mutant NMDAR. The presenceof anti-NMDAR antibodies was evaluated using both X200 and X10 dilutionsof the serum samples. Mutant GluRζ1(NR1, GluN1) subunits of NMDAR alonewere expressed on the cell surface and direct evidence was obtained ofthe presence or absence of autoantibodies recognizing extracellularepitopes of GluRζ1 and the induction of internalization byautoantibodies in the serum of study patients.

D-Serine Clinical Trial

Out of the seventeen patients that entered the study, the serum of onepatient was strongly positive at both serum sample dilutions for thepresence of both IgG and IgM classes of anti-NR1 NMDAR antibodies. Thepatient was a 67 year old single female having a diagnosis ofschizophrenia according to DSM-IV-R criteria (American PsychiatricAssociation, 2000 Diagnostic and Statistical Manual of MentalDisorders—(DSM-IV-TR), 4th edition. American Psychiatric AssociationWashington D.C. (Text Revision)). There was no history of mentaldisorder in the patient's family. The patient had completed post-highschool studies and had worked as a secretary. At age 27, after a periodof continuous headaches, for which no organic basis had been found, shehad abruptly developed an acute psychosis characterized by grandiose andparanoid delusions, mystical thinking, elated affect and agitation. Shehad been hospitalized in a psychiatric hospital and underwent treatmentwith antipsychotic drugs and electroconvulsive therapy with only partialresponse. The patient had never returned to her previous functionallevel, and except for short attempts at living in the community, hasbeen hospitalized ever since. She has been refractory to treatment withvarious classes of antipsychotic drugs, was not diagnosed with anymedical or neurological disorder and was maintained on sulpiride 50mg/day, citalopram 40 mg/day, lorazepam 1 mg/day and promethazine 50mg/day.

Following the demonstration of anti-NMDAR antibodies, the patient wasentered in an 8 week clinical trial with adjuvant DSR treatment. DSR isanaturally occurring amino acid that acts in vivo as anobligatoryco-agonist at the glycine modulatory site associated withNMDAR. No significant adverse events have been observed with DSR atdoses of ≦4 g/day. Both acute and chronic administration of 1-2 g DSR inhumans is known to result in ≧100 times increases in DSR serum levels(Kantrowitz et al., 2010, Schizophr Res121:125-30; Heresco-Levy et al.,2005, Biol Psychiatry 57:577-85).

The trial consisted of two periods, starting with a 2 weeklead-in/stabilization period (−2-0) following which the patient wasentered in the second period of the study which consisted of a 6 week(0-6), open-label, fixed dose therapy phase. During this phase, thepatient received adjuvant treatment with DSR, whose dose was increasedfrom 1500 mg/day (week 1) to 2000 mg/day (weeks 2 and 3) to 3000 mg/day(weeks 4 and 5) and to 4000 mg/day (week 6). The doses of the ongoingmedication received by the patient remained fixed throughout the studyand no changes in medication were performed.

The patient underwent prior to entering the study and at study weeks 3and 6 a medical work-up including complete medical history, and routineclinical blood work, including blood count+differential, lipids, andglucose levels, kidney, thyroid, and liver function parameters,urinalysis, and blood pressure measurements. Abdominal ultrasound wasperformed prior to study entry and electroencephalogram (EEG) and brainmagnetic resonance imaging (MRI) were obtained pre- and post-DSRadministration.

The assessment procedures used in the study included clinical andneurocognitive examinations. Motor and psychiatric symptoms as well asside-effects were rated biweekly throughout the study. The followinginstruments were used: 1) Positive and Negative Syndrome Scale (PANSS)(Kay et al., 1987, Positive and Negative Syndrome Scale (PANSS) ratingmanual. San Rafael Calif.: Social and Behavioral Sciences Documents); 2)Quality of Life Scale (QLS) (Wilkinson et al., 2000, Self-report qualityof life measure for people with schizophrenia: the SQLS. Br J Psychiatry177:42-6); 3) Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976,ECDEU Assessment Manual for Psychopharmacology-Revised. Rockville, Md.:US Dept. of Health, Education and Welfare); 4) Simpson Angus Scale forExtrapyramidal Symptoms (SAS) (Simpson and Angus, 1970, Acta PsychiatrScand Suppl. 212:11-9); and 5) Udvalg for Kliniske Undersøgelser (UKU)Side Effect Rating Scale (Lingjaerde, et al., 1987 Acta Psychiatr ScandSuppl 334:1-100). In conjunction with UKU ratings, patient's vital signsand body weight were monitored throughout the study.

In addition, cognitive performance was assessed pre- and post DSRtreatment. For this purpose, a 1.5-hour neurocognitive assessmentbattery (nine computerized and two paper/pencil tests) was employed thatmeasures accuracy and speed of performance in major cognition domains,including attention/vigilance, planning, short-term and working memory,decision making, abstraction and mental flexibility. All the tests wereformatted like games and puzzles, and were administered to the patientas part of the comprehensive neuropsychiatric assessment at baseline andthe end of study. The neurocognitive battery included the 1) Test ofAttentional Vigilance (TOAV, (Forbes, 1998, Journal of ClinicalPsychology 54:461-476; Greenberg, 1993, Journal of Child Psychology andPsychiatry 34: 1019-30)); 2) Tower of London (TOL, (Shallice, 1982,Specific impairments of planning. Philosophical Transactions of theRoyal Society of London. Series B, Biological Sciences 298:199-209);3-4) Digit Span Test (DST, forward and backward (Wechsler 1997, TheWechsler adult intelligence scale-III. San Antonio, Tex.: PsychologicalCorporation; Kaplan 1991, The WAIS-R as a neuropsychological instrument.San Antonio, Tex.: The Psychological Corporation; Lamar et al., 2007,Neuropsychologia 45:245-54; Lamar et al., 2008, Neuropsychologia46:2597-601)); 5-6) Corsi Block Tapping Test (CBTT, forward andbackward, (Corsi, 1972, Dissertation Abstracts International. 34:819B;Kessels et al., 2000, Applied Neuropsychology 7:252-58, Kessels et al.,2008, Assessment 15:426-34)); 7) Flanker Task (Erikson and Eriksen,1974; Perception & Psychophysics 25: 249-63, Stins et. al., 2007,Advances in Cognitive Psychology 3:389-96); 8) Time Wall (Perez et al.,1987, Unified Tri-services cognitive performance assessment battery:review and methodology; DTIC Document ADA181697,http://www.dtic.mil/dtic/tr/fulltext/u2/a181697.pdf); and 9) WisconsinCard Sort Test (WCST, (Berg, 1948, J Gen Psychol39:15-22; Nelson, 1976,Cortex 12:313-24)). In addition to the nine computerized tests, thepatient completed two paper/pencil tests: 10-11) part A and part B ofthe Trail-Making-Test (TMT, (Reitan, 1958, Percept. Mot Skills 8:271-76;Reitan, 1992 Trail Making Test: Manual for administration and scoring.Tucson, Ariz.: Reitan Neuropsychology Laboratory)) according to theguidelines presented by Spreen and Strauss (1998)). All neurocognitivetesting was completed in a private and quiet setting to limit anydistractions. The tests instructions were displayed and read to thepatient by a Ph.D.-level trained researcher.

Results

Baseline medical and neurological examinations and clinical laboratoryparameters of the patient were unremarkable with the exception of highprolactin and CMV IgG (76 U/mL) and EBV IgG (>750 U/mL) levels.Abdominal ultrasound examination showed no ovarian teratoma, which hasbeen described among anti-NMDAR encephalitis patients (Dalmau et al.,2011, Clinical experience and laboratory investigations in patients withanti-NMDAR encephalitis. Lancet Neurol 10:63-74) or other spaceoccupying lesions. The baseline EEG showed a normal EEG backgroundactivity with superimposed semi-rhythmic diffuse delta frequency burstsmore predominant over the right fronto temporal areas (FIG. 1 and FIG.2). This type of pattern, denominated “extreme delta brush” (EDB) hasbeen described in patients with NMDAR encephalitis and is consistentwith the relative frontal and temporal glucose hypermetabolism describedin some of these patients. Baseline brain MRI evidenced Fluid AttenuatedInversion Recovery (FLAIR) and T2 signal hyperintensities in theperiventricular white matter, subcortically, and deep bifrontally andbiparietally in the cortex. These type of findings have also beendescribed in anti-NMDAR encephalitis. No hypophysis-related pathologicalfindings were found.

DSR treatment was well tolerated throughout the study and no sideeffects were registered. As shown in Table 1, the quality of life of thepatient improved considerably during treatment with DSR, resulting bythe end of the treatment period in an ˜3 times reduction in terms ofreported symptoms and side effects. The patient entered the study havinga relatively high PANSS total score of 97, including significantpositive, negative, and general psychopathology symptoms. All thesesymptom domains improved during treatment with DSR and overall the totalPANSS score registered by the end of the study was lower by 17%.Although motor symptomatology, as measured by AIMS and SAS scores, wasminimal at baseline improvements were registered also in this domainfollowing DSR administration (Table 1).

TABLE 1 Quality of life, psychiatric and motor symptoms of patientpositive for anti NR1 NMDAR antibodies during 6 weeks treatment withD-serine. Study Week Outcome Measure 0 2 4 6 QLS Psychosocial 60 55 5038.33 Motivation/energy 42.86 42.86 42.86 42.86 Symptoms/side-effects15.63 9.38 9.38 3.13 PANSS Positive 24 21 21 19 Negative 18 19 17 16General 55 54 51 45 Total 97 96 89 80 AIMS 1 0 0 0 SAS 5 4 4 3Abbreviations: QLS, Quality of Life Scale; PANSS, Positive and NegativeSyndrome Scale; CGI, Clinical Global Impression; AIMS, AbnormalInvoluntary Movement Scale; SAS, Simpson Angus Scale for ExtrapyramidalSymptoms.

The neurocognitive performance data of the patient pre- and post-DSRadministration are shown in Table 2. Overall, DSR treatment had afavorable effect upon cognitive performance, as measured by the employedtest battery, with evident improvements in the domains of workingmemory, abstraction and mental flexibility. While at baseline thepatient could not comprehend/perform the DST, TMT and WCST tasks, thesetests were successfully completed post-DSR treatment (Table 2).

TABLE 2 Neurocognitive performance of patient positive for anti NR1NMDAR antibodies pre-and post-6 weeks treatment with D-serine Pre- Post-Neurocognitive Test Treatment Treatment TOAV Omission errors 1 2Commission errors 1 0 Response time, mean ± SD 562 ± 103 523 ± 93 (milliseconds) TMT Part A (seconds) 42 60.71 ToL ToL correctly solvedtrials, 6 4 total (0-12) ToL preplanning time, 15.48 ± 4.43  11.24 ±4.73  mean ± SD (seconds) ToL movement execution  22.57 ± 11.998 19.30 ±15.42 time, mean ± SD, (seconds) ToL total time (0-720 456.582 366.415seconds) DST Span Length (3-9) 6 7 Forward Number Correct (0-14) 8 9CBTT Span Length (2-9) 5 4 Forward Number Correct (0-16) 8 6 DST SpanLength (3-9) —* 4 Backward Number Correct (0-14) —* 3 CBTT Span Length(2-9) 4 3.5 Backward Number Correct (0-16) 6 5 Flanker Congruousresponse time, 725.03 ± 130.03 651.93 ± 130.16 Task mean ± SD(milliseconds) Congruous accuracy, 0.475 ± 0.499  0.65 ± 0.476 mean ± SD(proportion correct) Incongruous response time, 737.38 ± 131.34  713.3 ±102.14 mean ± SD (milliseconds) Incongruous accuracy, 0.450 ± 0.4990.575 ± 0.494 mean ± SD (proportion correct) Neutral response time,732.18 ± 127.96 688.23 ± 99.19  mean ± SD (milliseconds) Neutralaccuracy, mean ± 0.475 ± 0.499  0.65 ± 0.476 SD (proportion correct)Time Wall correctly estimated trials, 12 6 total (0-20) accuracy score,mean ± SD 0.056 ± 0.053 0.077 ± 0.051 TMT Part B (seconds) 102 86.35WCST Category Score —* 5 Trials to complete 1^(st) —* 12 category Totalcorrect score % —* 81.25 Total error score % —* 18.75 Abbreviations:TOAV, Test of Attentional Vigilance; TMT, Trait-Making-Task; ToL, Towerof London; DST, Digit Span Test; CBTT, Corsi Block Tapping Test; WCST,Wisconsin Card Sorting Test. —*, subject unable to complete task.

A response to DSR treatment, consisting of an attenuation of the EDBpattern, was also registered in terms of the EEG parameters registeredpre- and post-DSR administration (FIG. 1 and FIG. 2). A significantreduction in current latency of EDB over the right frontal area wasregistered following DSR treatment (t=2.686, df=113, p=0.0083, 95%confidence interval) (FIG. 3).

Remarkably, short-term DSR treatment resulted in significantly improvedquality of life, including reduction in psychopathology symptoms,improved motor symptomatology, improved cognitive performance, includingimproved working memory, abstraction and mental flexibility.

Example 3 In Vitro Efficacy of NMDAR Agonists in Anti-NMDAR Encephalitis

Rodent neuron cell cultures are treated with anti-NMDAR antibodies asdescribed in Hughes E G et al., J Neurosci 2012 30(17):5866-75.D-Serine, for example at a concentration of 50-200 uM, or Glycine, at aconcentration of 100-500 uM is added to some of the cultures, reversingreceptor intracellular localization. The determination of receptorslocalization and other relevant measures is based on histologicalmeasurements.

Immunohistochemical methods will be applied to document (a) localizationof NMDAR and NR1 and NR2 subunits; (b) loss of oligodendrocytes; (c)changes in astrocytes (S100beta) and microglia (cd11b), (d) expressionof neurotrophic factors: brain derived neurotrophic factor (BDNF), nervegrowth factor (NGF) and ciliary neurotrophic factor (CNTF); (e) markersof neurogenesis-doublecortin (17) and apoptosis-caspase3 (9).Quantification of histological measurements is based on images inseveral cortical subregions, striatum, globus pallidus, substantianigra, hippocampus, and cerebellum.

It will be evident to those skilled in the art that the invention is notlimited to the details of the foregoing illustrative examples and thatthe present invention may be embodied in other specific forms withoutdeparting from the essential attributes thereof, and it is thereforedesired that the present embodiments and examples be considered in allrespects as illustrative and not restrictive, reference being made tothe appended claims, rather than to the foregoing description, and allchanges which come within the meaning and range of equivalency of theclaims are therefore intended to be embraced therein.

It will be understood by those skilled in the art that various changesin form and details may be made therein without departing from thespirit and scope of the invention as set forth in the appended claims.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed in the scope of the claims.

In one embodiment of this invention, “about” refers to a quality whereinthe means to satisfy a specific need is met, e.g., the size may belargely but not wholly that which is specified but it meets the specificneed of cartilage repair at a site of cartilage repair. In oneembodiment, “about” refers to being closely or approximate to, but notexactly. A small margin of error is present. This margin of error wouldnot exceed plus or minus the same integer value. For instance, about 0.1micrometers would mean no lower than 0 but no higher than 0.2. In someembodiments, the term “about” with regard to a reference valueencompasses a deviation from the amount by no more than 5%, no more than10% or no more than 20% either above or below the indicated value.

In the claims articles such as “a”, “an” and “the” mean one or more thanone unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” or “and/or” betweenmembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention also includes embodiments in which more than one, or all ofthe group members are present in, employed in, or otherwise relevant toa given product or process. Furthermore, it is to be understood that theinvention provides, in various embodiments, all variations,combinations, and permutations in which one or more limitations,elements, clauses, descriptive terms, etc., from one or more of thelisted claims is introduced into another claim dependent on the samebase claim unless otherwise indicated or unless it would be evident toone of ordinary skill in the art that a contradiction or inconsistencywould arise. Where elements are presented as lists, e.g. in Markushgroup format or the like, it is to be understood that each subgroup ofthe elements is also disclosed, and any element(s) can be removed fromthe group. It should be understood that, in general, where theinvention, or aspects of the invention, is/are referred to as comprisingparticular elements, features, etc., certain embodiments of theinvention or aspects of the invention consist, or consist essentiallyof, such elements, features, etc. For purposes of simplicity thoseembodiments have not in every case been specifically set forth in haecverba herein. Certain claims are presented in dependent form for thesake of convenience, but Applicant reserves the right to rewrite anydependent claim in independent format to include the elements orlimitations of the independent claim and any other claim(s) on whichsuch claim depends, and such rewritten claim is to be consideredequivalent in all respects to the dependent claim in whatever form it isin (either amended or unamended) prior to being rewritten in independentformat.

1. A method of enhancing NMDAR-mediated neurotransmission in a disease associated with NMDAR antibody production, said method comprising administering an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor or a combination thereof to said subject.
 2. A method of mitigating the severity of, mitigating the pathogenesis of, lowering the incidence of or treating a disease associated with NMDAR antibody production, said method comprising administering an agent, which is a n NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor or a combination thereof to said subject.
 3. The method of claim 1, wherein said disease associated with NMDAR antibody production is paraneoplastic autoimmune encephalitis.
 4. The method of claim 1, wherein said disease associated with NMDAR antibody production is non-paraneoplastic autoimmune encephalitis.
 5. The method of claim 1, wherein said disease associated with NMDAR antibody production is anti-NMDAR encephalitis.
 6. The method of claim 5, wherein said NMDA receptor-associated encephalitis is associated with occult tumor.
 7. The method of claim 6, wherein said tumor is an ovarian teratoma.
 8. The method of claim 6, wherein said method further comprises the step of removing said tumor, providing immunotherapy or a combination thereof.
 9. The method of claim 1, wherein said agent is glycine (GLY), D-serine, D-cycloserine (DSR), or a combination thereof.
 10. The method of claim 1, wherein said agent is D-serine and is administered at a dosage of 30-60 mg/kg/d.
 11. The method of claim 1, wherein said agent is Glycine and is administered at a dosage of 40-60 g/d.
 12. The method of claim 1, wherein said agent is D-cycloserine and is administered at a dosage of 250-1000 mg/d.
 13. The method of claim 1, wherein said agent is Bitopertin and is administered at a dosage of 10-40 mg/d.
 14. The method of claim 1, wherein said agent is Benzoic acid and is administered at a dosage of 500-2000 mg/d.
 15. The method of claim 1, wherein said method is utilized during an acute stage of a disease associated with NMDAR antibody production.
 16. The method of claim 1, wherein said method is utilized during a rehabilitational stage of a disease associated with NMDAR antibody production.
 17. The method of claim 1, wherein said method further comprises treating said subject with an adjunct cognitive treatment regimen. 